Novel Interventions Against HPV-associated Neoplasia

描述（由申请人提供）：人乳头瘤病毒（HPV）是感染各种上皮组织的小DNA病毒。肛门生殖器HPV的一个子集，包括HPV-16和18基因型的“高风险”HPV，与几乎所有宫颈癌，以及大多数其他肛门生殖器癌和头颈癌的一个子集相关。在美国，每年有超过30，000例新癌症由高危HPV感染引起。目前治疗这些癌症的方案依赖于几十年前的策略。晚期癌症的五年生存率仍然很低。最近FDA批准的HPV疫苗有望预防新的感染，但直到2040年及以后才能对癌症发病率产生影响。因此，仍然迫切需要开发用于治疗和/或预防HPV相关癌症的改进的手段，从而提高存活率并减少患病者的痛苦。MMHCC申请的目标是确定新的，更有效的治疗和预防HPV阳性癌症的方案。我们将利用在相关组织中表达HPV 16 E6和E7癌基因的基因工程小鼠品系作为临床前模型，以实现这些目标。这些小鼠已被用于建立HPV相关宫颈癌和头颈癌的有效模型。将追求三个主要目标：1）研究抗雌激素在宫颈癌治疗和预防中的应用，2）验证用于治疗HPV相关癌前病变和癌症的激酶靶点，以及3）开发针对HPV相关癌症的有效免疫疗法。

DESCRIPTION (provided by applicant): Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with nearly all cervical carcinomas, as well as the majority of other anogenital cancers and a subset of head and neck cancers. Each year in the US, over 30,000 new cancers arise from high-risk HPV infections. Current regimens for treating these cancers rely on decades old strategies. Five-year survival rates for advanced grade cancers remain low. A recently FDA-approved HPV vaccine holds promise in preventing new infections, but it will not have an impact on cancer incidence until 2040 and beyond. Therefore there remains an urgent need to develop improved means for treating and/or preventing HPV-associated cancers and thereby increase survival rates and decrease suffering among those afflicted. The goal of this MMHCC application is to identify new, more effective regimens for treating and preventing HPV-positive cancers. We will make use of genetically engineered mouse strains that express the HPV16 E6 and E7 oncogenes in relevant tissues as the preclinical model in which to pursue these goals. These mice have been used to establish well-validated models for HPV associated cervical cancer and head and neck cancers. Three major goals will be pursued: 1) investigate the use of anti-estrogens in the treatment and prevention of cervical cancer, 2) validate kinase targets for therapy of HPV associated premalignant lesions and cancer, and 3) develop effective immunotherapies against HPV-associated cancers.